Epithelial cancer of the aerodigestive tract is a tremendous problem throughout the world because of its increasing incidence and the difficulty of treating it once the tumor has developed. The overall goal of this program project grant is to develop effective chemopreventive approaches to reduce the incidence of human aerodigestive epithelial cancers, especially in those individuals who are at high risk. In order to make significant progress toward these goals, clinical studies and laboratory studies must be focused and closely integrated into a well-coordinated program. Specifically, this program encompasses three major directions: 1. Identification of Effective Chemopreventive Agents in Two Comprehensive Clllinical Trials: Project 1. Chemoprevention Trial to Prevent Second Primary Tumors with Low-Dose 13-cis Retinoic Acid in Head and Neck Cancer. Project 3. Chemoprevention Trial in Oral Premalignancy. 2. Identification and Determination of Relative Impact of Risk Factors for the Development of Aerodigestive Epithelial Cancers: Project 2. Genetic Susceptibility to Second Primary Tumors: The Quantitative Risk Assessment Model. 3. Understanding of the Fundamental Events of Biological Processes During Carcinogenesis and the Mechanisms of Action of Retinoids: Project 4. Field Cancerization: Cellular and Molecular Test of Hypothesis. Project 5. Molecular Determinants of Growth and Differentiation of Head and Neck Tumors. Project 6. Role of Nuclear Retinoic Acid Receptors in the Mechanism of Response of Malignant Oral Mucosa Cells to Retinoids. Five core components (Administration, Biostatistics/Data Management Center, Analytical Chemistry, Histology Laboratory, Nutritional Epidemiology, and Clinical Adherence) provide the structure and expertise required for the successful integration and execution of combined clinical trials and laboratory studies.